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A participant in the Breakfree-2 phase I study of the CAR-T therapy zola-cel died of septic pneumonia 44 days after treatment. Investigators have not established the cause of the event, which occurred after high-dose cyclophosphamide was given to target circulating CAR-T cells. The study also reported potential signs of benefit, but its small, early-stage results require cautious interpretation.
A participant in the phase I Breakfree-2 study of the experimental CAR-T therapy zolacabtagene autoleucel (zola-cel) died of septic pneumonia 44 days after treatment, according to findings presented October 24. The death, which occurred after the trial’s June 2026 data cutoff, is under investigation; the study presenter said its cause is not fully understood.
The participant had highly active relapsing multiple sclerosis and developed rigidity and tremor on day 17 after receiving zola-cel. The patient received intermittent corticosteroids and intravenous immunoglobulin. On day 41, clinicians administered high-dose cyclophosphamide to target circulating CAR-T cells after no alternative cause for the symptoms was identified. Septic pneumonia developed on day 43, and the patient died the following day.
Jeffrey Cohen, MD, of the Cleveland Clinic Mellen Center, presented the findings at MSToronto2026, a joint meeting of the European and Americas committees for multiple sclerosis research. He said the patient’s CAR-T cell expansion was in line with that of other participants. The fatal event was not reported as ICANS, or immune effector cell-associated neurotoxicity syndrome, and remains under investigation.
Breakfree-2 included 66 participants in its MS cohorts: 30 with highly active relapsing disease and 36 with progressive MS. The trial’s primary focus was safety and tolerability, with efficacy as a secondary measure. In the reported data, cytokine release syndrome occurred in 42.4% of participants and ICANS in 7.6%; most cases were mild and resolved within a median of two days. One grade 4 ICANS event in a participant with progressive MS resolved within four days after treatment.
Safety Questions for MS CAR-T
The death adds a serious safety event to evidence from an early trial of a cell therapy being studied for people whose MS may remain active or worsen despite available treatments. CAR-T therapy is an investigational approach in this setting, and the fatal event underscores why safety monitoring and investigation matter as researchers evaluate its risks.
The event also followed administration of high-dose cyclophosphamide, but the reported information does not establish that the drug, the CAR-T treatment, infection, or another factor caused the death. That distinction matters: the case is a reported fatal event during the trial, not a confirmed explanation of the mechanism or a finding that applies to all CAR-T products.
The results also included early measures that may interest researchers and patients, such as participants remaining off disease-modifying therapies at follow-up and reported stability in disability among many progressive-MS participants. These observations do not establish long-term benefit. The study is small, open-label and uncontrolled, and the presenter cautioned that efficacy findings need careful interpretation.
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What Breakfree-2 Was Testing
Breakfree-2 studied zola-cel, a CD19-directed CAR-T cell therapy intended to deplete B cells. The MS presentation covered two groups: people with highly active relapsing MS and people with progressive MS. The trial also included a separate refractory myasthenia gravis cohort, but the presentation described here focused on the MS groups.
Participants received lymphodepletion with fludarabine and cyclophosphamide before a single zola-cel infusion. The study evaluated two dose levels, although the supplied report lists the same numerical cell dose for both, so the difference between those levels is not clear from that account. In September, developer Bristol Myers Squibb paused its zola-cel program to evaluate safety findings, according to the report. Around the same time, Novartis reported three fatal ICANS cases in separate autoimmune CAR-T trials of rapcabtagene autoleucel; those cases involved a different product and are not evidence about the cause of the Breakfree-2 death.
“The pathogenesis of that event is not fully understood.”
— Jeffrey Cohen, MD, of the Cleveland Clinic Mellen Center, at MSToronto2026
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Cause of Death Still Under Review
The cause and pathogenesis of the death have not been determined, and Cohen said the event is still being investigated. The available account does not clarify whether septic pneumonia resulted from treatment-related immune effects, cyclophosphamide, another infection risk, or a combination of factors. It also does not provide a final investigator or regulator assessment.
The report says no other grade 5 events were reported in the trial or among 190 people treated with zola-cel in phase I autoimmune-disease studies. That comparison does not settle the cause of this case or predict risk for future patients. Follow-up duration, the full safety dataset and any updated findings from the paused program were not provided in the material.
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Investigation and Program Review
Investigators are continuing to examine the fatal event, while Bristol Myers Squibb’s zola-cel program was reported paused for a safety evaluation. The next relevant developments would include findings from that review, any updated safety disclosures, and information about whether or how trial activity will proceed.
Readers should also look for longer follow-up from Breakfree-2 and fuller reporting of its safety and efficacy results. Until investigators provide more detail, the cause of the death remains unresolved, and the early efficacy observations should not be treated as proof that zola-cel is effective or safe for people with MS.
Key Questions
What happened to the participant in the zola-cel study?
The participant developed motor symptoms 17 days after treatment, received high-dose cyclophosphamide on day 41, developed septic pneumonia on day 43 and died on day 44. The event is under investigation.
Has the cause of death been established?
No. The study presenter said the event’s pathogenesis is not fully understood. The reported information does not establish whether zola-cel, cyclophosphamide, infection risks or another factor caused the death.
Was the death attributed to ICANS?
No. The report states that the death was not related to ICANS. The fatal event was reported as septic pneumonia, though its underlying cause remains under review.
What did the study report about other safety events?
Across the reported Breakfree-2 data, 42.4% of participants had cytokine release syndrome and 7.6% had ICANS. Most cases were grade 1 or 2 and resolved within a median of two days; one grade 4 ICANS event resolved within four days after treatment.
Does the study show that zola-cel works for MS?
It reported early observations, including participants remaining off disease-modifying therapies at follow-up and stability or improvement in disability for many participants with progressive MS. The trial was small, open-label and uncontrolled, so its presenter said efficacy results require caution; the findings do not establish long-term benefit.
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